Atopic dermatitis is an increasingly common pruritic, chronic, inflammatory skin disorder. There has been a striking rise in the incidence of Atopic dermatitis (AD) during the past two decades, which is not simply due to an increased recognition of the disease. Population studies suggest that in most countries, AD now affects at least 10-20% of children at some point during childhood. In particular, higher prevalence has been recorded in urban regions than in rural regions of development countries, and the disease is more common in higher social class groups, suggesting that environmental factors associated with more industrialized and urban living determine expression of AD.
There are pathogenic mechanisms that are in common to both AD and asthma. The exaggerated inflammatory response (including increased production of IgE and eosinophilia) to environmental triggers, including irritants and allergens is characteristic of both AD and asthma. Total IgE levels are elevated in both AD and asthma. Genetic studies have demonstrated common chromosomal linkages between AD and asthma.
Leukotrienes (LTs) are a class of potent biological inflammatory mediators derived from arachidonic acid through the 5-lipoxygenase pathway Leukotrienes are divided into two groups according to their chemical structure: those with a sulphur linkage (cysteinyl LTs: LTC4, LTD4, LTE4), and those that lack one (LTB4). Eosinophils, basophils and mast cells are the most important sources of LTs. Epidermal cells are able to transform neutrophil derived LTA4 into LTB4 and LTC4. Thus the epidermis can also contribute significantly to LT synthesis. It has been shown that cysteinyl leukotrienes (cysLTs) mediate asthma and allergic rhinitis and when the LT receptors are antagonized, symptoms resolve. Leukotrienes are important pro inflammatory mediators that are capable of inducing airway smooth muscle constriction, airway hyper responsiveness, eosinophil migration, vascular permeability, edema, and chemotaxis. A role for LTs in AD has been suggested in the literature. There is evidence of enhanced LT production in the pathogenesis of AD. The cysteinyl LTs increase vascular permeability and dilate skin blood vessels. LTC4 has been found in the skin of AD patients using the suction blister technique. Patients with AD have activated circulating basophils and increased basophil releasability of LTC4. Cysteinyl LT release from basophils and cosinophils isolated from AD patients is increased compared to healthy controls. Enhanced spontaneous and stimulated release ability of LTC4 from leukocytes of patients with AD compared with normal controls has been reported. Increased production of LTs has been reported in the skin of atopic patients after allergen specific challenge.
There are at least two types of LT receptors: cysLT1 and cysLT2. Montelukast (Singulair®, Merk-Frosst), zafirlukast (Accolate®, Zeneca), and pranlukast (Ultair®, SmithKline Beecham) are LT receptor antagonists that demonstrate high-affinity binding to the cysLT1 receptor. Montelukast is currently indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older and for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older. Montelukast is generally a safe drug during long term treatment; side effects are minimal. Asthma and allergic rhinitis have numerous pathophysiological elements in common with AD, and together these three diseases are referred to as the “atopic triad”. As outlined above there are pathogenic mechanisms that are central to both AD and asthma. Evidence in the literature provides a pathophysiological rationale for the use of cysLT receptor blockers in the treatment of AD however the exact mechanism of action of leukotriene receptor antagonists in AD is not known. Intradermal LTD4 causes a wheal-and-flare response that could be blocked by a LTD4 antagonist. Montelukast has been shown to decrease eosinophils by 15%. LTD4 stimulates proliferation of eosinophil hematopoietic progenitor cells, and this increase can be suppressed by Montelukast.
The major function of the skin is to protect the body against physical and chemical injury and to prevent loss of body water and other substances. The stratum corneum (SC) is the outmost layer of the skin which is being continually replaced. By so doing the skin is well adapted to its requirements for repairing damage from wear and tear. However, in Atopic Dermatitis environmental and individual factors interact in a complex manner to induce skin abnormalities and dryness. Application of moisturizers to the skin induces changes in its superficial as well as deep layers. The chemical and physical characteristics of the individual ingredients of the formulation determine the performance of the drug product.
Moreover, in topical treatments of dermatological conditions the efficacy is likely to depend on the dosage, where compliance is a great challenge faced in the management of the diseases.
Montelukast sodium exerts additional challenge to be formulated in a semi solid formulation even for experienced formulators.
Sodium montelukast (Singulair), chemically known as [sodium 1-(1-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)-phenyl)(3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl) thio)-methyl)-cyclo-propane) acetate is a photosensitive compound requiring special handling precautions to protect specimens from light especially in a solution.
In the montelukast molecule there are number of functional groups that impair the chemical stability of this substance. Montelukast is known to be prone to the formation of several types of impurities:    1. a sulfoxide impurity: [1-[((RS)[1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl)phenyl)-3-[2-(1-hydroxy-1-methylethyl)phenyl)propyl] sulfinyl] methyl] cyclopropyl]acetic acid;    2. a diol impurity: 2-(2-(3-(S)-(3 (E)-(2-(7-Chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol;    3. a methyl styrene impurity: [1-[[[(1 R)-1-[3-[(E)-2-(7-Chloroquinolin-2-yl)etheny[ ]phenyl]-3-[2-(1-methylethenyl)phenyl]propyl] sulfanyl]melhyl] cyclopropyl] acetic acid (USP imp F);    4. a cis-isomer impurity: [1-[[[(1 R)-1-[3-[(Z)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl] sulfanyl]methyl] cyclopropyl] acetic acid;    5. a Michael adduct impurity (1): 1-[[((1 R)-1-[3-[(1 R)-1 [[[1-(Carboxymethyl)cyclapropyl]methyl] sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]suifanyl]methyl]cyclopropyllacetic acid;    6. a Michael adduct impurity (2): 1-[[[(1 R)-1-[3-[(1 S)-1-[[[1-(Carboxymethyi)cyclopropyl]methyl] sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid;    7. a methyl ketone impurity: [1-({((1R)-3-(2-acetylphenyl)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl)phenyl]propyl]sulfanyl] methyl] cyclopropyl]acetic acid.